Spinal cord injury (SCI) is a devastating trauma for which there currently is no cure. SCI triggers a robust inflammatory response that is dominated by activated CNS macrophages. Data suggests that modulating macrophage activity after SCI can limit delayed neurodegeneration and promote functional recovery. Studies in this proposal will examine whether Toll-like receptor (TLR)4 activation of macrophages influences the survival of mature and immature myelinating cells in the spinal cord, i.e., oligodendrocytes and oligodendrocyte progenitor cells (OLs and OPCs) (Aim 1). All studies will be conducted in vivo using a clinically-relevant model of spinal cord injury (SCI) in mice lacking functional TLR4 signaling. A combination of microsurgical, immunohistochemical, image analysis and molecular techniques will be used to asses OL/OPC survival and changes in production of molecules that may be associated with TLR4 signaling and myelination. Also, studies in Aim 2 will use wild-type SCI mice to determine whether priming of spinal cord macrophage activation via TLR4 can limit demyelinating pathology after SCI. If successful, these studies would reveal a potential target for therapy in individuals with SCI.